{\rtf1\ansi\ansicpg1252\deff0\deflang1033{\fonttbl{\f0\fswiss\fcharset0 Arial;}} {\*\generator Msftedit 5.41.15.1515;}\viewkind4\uc1\pard\f0\fs21 Project Summary: The Colorectal Cancer Family Registry - Seattle (CCFR -S), a center within the\par multinational six-site Colon CFR consortium, is a population-based resource for studies of the genetics and\par genetic epidemiology of colorectal cancer. We are entering Phase III of this project, the largest ever cohort\par of colorectal cancer families. In this new application, we propose to continue to expand accrual of individuals\par with colorectal cancer who carry defective mismatch repair (MMR) alleles or who are at high risk of\par hereditary colorectal cancer due to other as-yet-unknown genetic variants. To facilitate further analyses of\par MMR-mutation carriers and to enable investigators to conduct more informative studies, such as those for\par gene mapping, in Amsterdam families who do not have evidence of an MMR defect, we will enroll families\par who carry an MMR or MYH mutation and families who meet the Amsterdam criteria without evidence of an\par MMR mutation (n=80). Probands will be recruited through a collaborative effort with the Gastrointestinal\par Cancer Prevention Program, an area wide high-risk clinic located at the Seattle Cancer Care Alliance, a joint\par Fred Hutchinson/UW/Seattle Children's facility. Eligible individuals will complete our standardized familyhistory\par and risk-factor interview and provide relevant biospecimens: blood (or buccal) samples and tumor\par blocks. We will support the Molecular Characterization Core activities by submitting participant biospecimen\par samples for: screening for expression of MLH1, MSH2, and MSH6 proteins; MMR-mutation testing guided by\par the IHC results; MLH1 methylation testing; screening for selected mutations in MYH; and testing for somatic\par mutations in BRAF. We will also continue to follow up, using active and passive protocols, our large existing\par cohort of probands and their relatives to evaluate and monitor: risk of developing new neoplasms; recurrence\par of original cancer; and mortality from colorectal cancer and other causes. We are currently conducting\par several ancillary studies focused on: gene hunting; gene-environment interactions; screening efficacy;\par behavioral changes; issues related to genetic disclosure; and the economics of screening and treatment.\par This proposal also includes studies to characterize the colorectal lesions that have been collected to date,\par including germline mutations in MLH1 and MSH2 and hypermethylation of the promoter region of MLH1.\par The CCFR - S is also responsible for taking the lead in the administrative coordination of all Colon CFR\par activities, including coordination of protocols and research agendas.\par Relevance: In collaboration with the other five Colon CFR centers, our registry is a valuable resource for\par translational research in the genetic epidemiology of colorectal cancer. The CCFR - S provides an important\par population-based perspective within our consortium studies of colorectal cancer.\fs20\par \par }